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World Journal of Pharmaceutical ReseaRch Volume 3, Issue 3, 4336- 4350.

Research Article

ISSN 2277 – 7105

ANTIMICROBIAL ACTIVITIES; IONIC LIQUID AND MICROWAVEASSISTED SYNTHESIS OF RING-SUBSTITUTED 3-(3-BROMO-4OXO-4H-CHROMEN-2-YL)-4H-CHROMEN-4-ONE Ajay M. Ghatole*1, Kushal R. Lanjewar2, Mahesh K. Gaidhane3 1

Dhote Bandhu Science College, Department Of Chemistry, Gondia 441614 , INDIA

2 3

Mohsinbhai Zawer College, Department Of Chemistry, Wadsa, Desaigang, INDIA

Institute of Science, Department Of Chemistry, Civil Lines, Nagpur 440001, INDIA ABSTRACT

Article Received on 05 March 2014, Revised on 28 March 2014, Accepted on 21 April 2014

An efficient procedure for the preparation of substituted 3-(3-(5chloro-2-hydroxyphenyl)-3-oxoprop-1-enyl)-6-methyl-4H-chromen-4one via the condensation of acetophenones with 6-sub-4-oxo-4Hchromene-3-carbaldehyde in the presence of catalytic amount of

*Correspondence for

ethylenediammonium diacetate (EDDA) using different ionic liquids at

Author

room temperature is described. The advantages of this method are

Ajay M. Ghatole

generality, high yield, short reaction times, ease of product isolation,

Dhote Bandhu Science

and ecologically friendly.A series of substituted 3-(3-bromo-4-oxo-4H-

College, Department Of Chemistry, Gondia 441614 ,

chromen-2-yl)-4H-chromen-4-one were prepared by the reaction of 3(3-(5-chloro-2-hydroxyphenyl)-3-oxoprop-1-enyl)-6-methyl-4H-

India

chromen-4-one in the presence of copper bromide and DMSO. A comparison of conventional heating and microwave irradiation in the synthesis of 3-(3bromo-4-oxo-4H-chromen-2-yl)-4H-chromen-4-ones is discussed. Microwave irradiation was found to increase the yields of the desired products, shorten the reaction time. The newly synthesized compounds were characterized on the basis of elemental analysis, IR, 1H NMR and mass spectra. All the synthesized compounds were tested for their antibacterial activities against Gram +ve and Gram –ve bacteria, and antifungal activities. Key Words: Chromone, acetophenone, aldehyde, ionic liquids, copper bromide, ethylenediammonium diacetate (EDDA), microwave .

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INTRODUCTION Natural products having a chromonic and flavonoidic structure exhibit important biological properties such as antiviral, cardioprotective, antioxidant, hepatoprotective, antitumoral and antiflammatory activities.[1] The 3-Formylchromone derivatives have been extensively used as versatile solution phase building blocks for the synthesis of a large number of heterocyclic systems. A number of 3-formylchromone[2] were synthesized by formylating 2-hydroxy acetophenone (Vilsmeier- Hack reaction). The most suitable formylating reagent is a complex of DMF and POCl3. A number of reports have appeared in the literature, describing the isolation of chromones (flavonoids) from various plants: roots stem, bark, heartwood, seeds, leaves, and flowers. These compounds exists in the free state as chromones or in the combined from as glycosides. 2-Phenyl chromones and other constitute of heartwood and bark are relatively stable “end products” which may some times functions as fugisides, insecticides, etc. 2-Aryl chromones are known to prevent the contraction of rabbit intestine and other muscles.[3] Chromones like querecetin and routine possesses vitamin ‘p’ activity and are use in the treatment of condition in which there is capillary bleeding due to an increased capillary fragility. RESULT AND DISCUSSION The strategy for the synthesis of substituted 3-(3-bromo-4-oxo-4H-chromen-2-yl)-4Hchromen-4-one(5a-j)

involves

the

preparation

of

substituted

3-(3-(5-chloro-2-

hydroxyphenyl)-3-oxoprop-1-enyl)-6-methyl-4H-chromen-4-one (4a-j) intermediates in the presence of copper bromide and DMSO. The substituted 3-(3-(5-chloro-2-hydroxyphenyl)-3oxoprop-1-enyl)-6-methyl-4H-chromen-4-one (4a-j) was prepared by the condensation reaction between substituted acetophenone and 6-sub-4-oxo-4H-chromene-3-carbaldehyde using different ionic liquids. The present method for the synthesis of 3-(3-(5-chloro-2-hydroxyphenyl)-3-oxoprop-1-enyl)6-methyl-4H-chromen-4-one (4b) has many obvious advantages over classical procedures, including being environmentally more benign, simple, the ease of product isolation, higher yield, shorter reaction time. In recent years, organic reactions in ionic liqids without using harmful organic solvents are of great importance especially in relation to today’s environmental concerns. On the other hand, organic reactions using reusable ionic liquids[5] have also received much attention because of their versatile and multifaceted characteristics. In continuation of our research in using ionic liquids as a green reaction medium for the

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condensation of carbonyl compounds with active methylene compounds catalyzed by ethylenediammonium diacetate (EDDA). The reaction was found to be general and applicable to aromatic aldehydes. The substituted acetophenone bearing various substituents such as chloro, nitro, methyl, etc. could successfully react with 6-sub-4-oxo-4H-chromone-3-carbaldehyde at room temperature within two hour with high yield. The examined ionic liquids general type [amine] [HSO4] and [Bmim]BF4, [Bmim]PF6 compared with the classical molecular solvents were all efficient and gave excellent results, with the advantage of rate acceleration and increase of yield which is depicted in table 1. Table 1. Selectivity proper solvent for synthesis of 3-(3-(5-chloro-2-hydroxyphenyl)-3oxoprop-1-enyl)-6-methyl-4H-chromon-4-one (4b).

S. Ionic liquid No 1

2

3

4

5

6

Solvent

DMF Toluene THF DMF [Bmim]BF4 Toluene THF Triethylamine DMF sulfate Toluene [Et3NH][HSO4] THF n-Tripropyl amine DMF sulfate Toluene [n-Pr3NH][HSO4] THF IsoPropylamine DMF sulfate [iso- Toluene PrNH2][HSO4] THF Ethanol/P Classical way iperidine [Bmim]PF6

Presence of EDDA (0.1mmole) Time (h) Yield (%)

Absence of EDDA Time(h)

2 72 3 75 2.5 70 2 70 3 73 2.5 69 2 65 3 67 2.5 66 3 66 3 66 3.5 64 3 62 3 63 3.5 60 The reaction mixture was kept (Yield 30%)

Yield (%)

4 25 5 28 6 19 4 22 5 28 6 21 4 23 5 25 6 20 6 22 7 24 6 20 7 22 7 20 7 20 for 35-400C for 2 h.

As we expected, the reaction could hardly proceed in the absence of EDDA. In conclusion, we have demonstrated that the condensation between 6-sub-4-oxo-4H-chromone-3carbaldehyde with active methylene compounds could be effectively performed at room temperature in the ionic liquids [Bmim]BF4 or [Bmim]PF6 catalyzed by EDDA.

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In this communication synthesis of [Bmim]BF4 , [Bmim]PF6 liquids of general type [amine] [HSO4]

[8]

[7]

and three different ionic

was synthesized by literature and has been utilized

for the comparative study. The influence of molar conc. of [Et3NH][HSO4], temperature, time was also recorded in case of 3-(3-(5-chloro-2-hydroxyphenyl)-3-oxoprop-1-enyl)-6-methyl-4H-chromon-4-one (4b) at 1000C in toluene. Water soluble ionic liquid was recovered by removing water under vacuum and oven dried after every cycle, table 2. The recycling efficiency of ionic liquid was found to be decreased after each cycle (Figure 1). Table 2: Effect of reuse of [Et3NH][HSO4] ionic liquid on the formation of 3-(3-(5chloro-2-hydroxyphenyl)-3-oxoprop-1-enyl)-6-methyl-4H-chromon-4-one (4b) at 1000C in toluene. Entry 1 2 3 4 5 6 7 8 9 10

Recycling 0 1 2 3 4 5 6 7 8 9

Time (h) 3 3 3 3 3 3 3 3 3 3

Isolated Yield % 75 73 71 70 69 67 66 64 63 62

Figure 1: Effect of reuse of [Et3NH][HSO4] ionic liquid on the formation of 3-(3-(5chloro-2-hydroxyphenyl)-3-oxoprop-1-enyl)-6-methyl-4H-chromon-4-one (4b)

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The IR spectra of compounds 4a-j showed peaks at 3450 cm-1 due the –OH function. Strong, sharp absorption bands observed at 1640-1670 cm-1 attributable to the carbonyl (–C=O), bands at 1564-1575 cm-1 suggested the presence of C=C group. In addition, bands were observed at 2880-3070 cm-1 corresponding to the –CH3 group. The 1H NMR spectra of compounds 4a-j displayed signals at δ 12.47-12.51due to the –OH. For compounds 4b, e and f, the singlet at δ 2.3-2.4 integrated for the – CH3 protons. 1H NMR spectra of compounds 4a-j revealed doublets at δ 7.78-8.30 indicating the presence of – CH=CH–group. An additional δ 5.3 singlet corresponding to two protons indicated the presence of an –NH2 group in compound 4i. The compounds 4a-j gives the satisfactory elemental analysis. The physicochemical data is depicted in table 4. Table 4: Physical characterization data of substituted 3-(3-(5-chloro-2-hydroxyphenyl)3-oxoprop-1-enyl)-6-methyl-4H-chromen-4-one (4a-j). S. No.

R

R1

R2

Yield (%)

m.p. (0C)

4a

Cl

H

Cl

65

166

4b

CH3

H

Cl

75

219

4c

Cl

Cl

Br

66

225

4d

Cl

Cl

H

69

230

4e

Cl

NO2

CH3

63

238

4f

CH3

Br

Cl

65

240

4g

Cl

Br

Cl

55

198

4h

CH3

Br

CH3

58

260

4i

Cl

H

NH2

60

177

4j

CH3

H

CH3

61

181

Mol. formula C18H10Cl2O4 C19H13ClO4 C18H9BrCl2O4 C18H10Cl2O4 C19H12ClNO6 C19H12BrClO4 C18H9BrCl2O4 C20H15BrO4 C18H12ClNO4 C20H16O4

(Calcd) (%) Found C H O 59.75 2.45 17.69 (59.86) (2.79) (17.72) 66.86 3.70 18.64 (66.97) (3.85) (18.78) 49.10 2.01 14.45 (49.13) (2.06) (14.54) 59.80 2.73 17.65 (59.86) (2.79) (17.72) 59.10 3.10 24.80 (59.16) (3.14) (24.89) 54.32 2.84 15,19 (54.38) (2.88) (15.25) 49.06 2.00 14.45 (49.13) (2.06) (14.54) 60.01 3.62 16.00 (60.17) (3.79) (16.03) 63.17 3.45 18.69 (63.26) (3.54) (18.73) 74.56 5.00 19.76 (74.99) (5.03) (19.98)

Despite of the high degree of research findings over diverse area, it is intriguing to design and develop new heterocycles having novel moieties like bis-chromone within a single molecule. Literature survey shed light on the pharmacological importance of chromone heterocycles and also upon the urgent need to develop some novel heterocycles that can act as inhibitor on

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various drug resistant pathogens. The title substituted 3-(3-bromo-4-oxo-4H-chromen-2-yl)4H-chromen-4-one (5a-j) have been prepared from the corresponding substituted 3-(3-(5chloro-2-hydroxyphenyl)-3-oxoprop-1-enyl)-6-methyl-4H-chromen-4-one(4a-j) intermediates in the presence of copper bromide and DMSO. Recently, much attention has focused on microwave assisted organic synthesis (MAOS) in the absence of a solvent. Often, thermal demanding reactions take hours in solution. However, with microwave irradiation these same reactions may be completed within a minute. In this study subsequent ring closing affords the desired 3-(3-bromo-6-chloro-4-oxo-4Hchromen-2-yl)-6-methyl-4H-chromen-4-one (5b), in most instances with either warming to ambient temperature or mild heating at 750C. This ring closing required more forcing conditions to proceed effectively. In (Scheme) the synthesis of desired product 5b was found to be exceedingly slow without heating above ambient temperature (7 h, ≤30%). Even heating at 750C for 7 h was found to be not optimal in providing the 3-(3-bromo-6-chloro-4oxo-4H-chromen-2-yl)-6-methyl-4H-chromen-4-one (5b). Scheme

Furthermore, short reaction time with heating in an oil bath at higher reaction temperature (Table 3) were found to result in comparatively good yield of the desired product and complete consumption of starting material. Microwave irradiation with heating to 1450C for 20 min promoted the formation of the desired 3-(3-bromo-6-chloro-4-oxo-4H-chromen-2-yl)6-methyl-4H-chromen-4-one (5b) in 64% yield. It is interesting to note that both microwave irradiation with heating at a lower temperature (750C for 30 min) and immersion of the

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reaction flask in an oil bath at 1450C for 4h and 750C for 7h provided less than optimal results. Table

3:

Synthesis

of

3-(3-bromo-6-chloro-4-oxo-4H-chromen-2-yl)-6-methyl-4H-

chromen-4-one (5b). Entry 1 2 3 4

Temp 75 145 75 145

Time 7h 4h 30 min 20 min

Heating Method Oil bath Oil bath Microwave reactor Microwave reactor

Yield (%) 30 45 50 64

The IR spectra of compounds 5a-j showed peaks at 2936-3045 cm-1 due to methyl group while the peaks at 540 cm-1attributed to C-Br group. A sharp band observed at 1680-1720 cm1

corresponding to the carbonyl (-C=O) function derived from flavanoid structure.

The 1H NMR spectra of compounds 5 b, e, and f revealed singlet at δ 1.8-2.3 ppm integrating for three protons of –CH3 group. The signals due the –OH group and corresponding doublets for –CH=CH- of chalcone structure did not appear. Additional signals at δ 7.02-8.2 ppm in aromatic region integrating due to 7 protons indicated the formation of hybrid molecules of quinoline appended with a flavanoid moiety strongly supported the structure. The 1H NMR spectra of compounds 5i having -NH2 group resonated at δ 5.3 ppm integrating for two protons as a singlet. The elemental analysis and molecular ion peaks of compounds 5a-j were consistent with the assigned structure. The physicochemical characteristics are well mentioned in table 5. The syntheses were carried out in a MW domestic oven adapted for the use of a reflux condenser, at constant power (400 W). All the reactions proceed to completion between 10 to 20 min and a longer time did not increase the yield.

Table 5: Physical characterization data of Substituted 3-(3-bromo-4-oxo-4H-chromen-2yl)-4H-chromen-4-one (5a-j). MW Time (min)

Yield (%)

m. p.

Mol. formula

Cl

10

76

120

C19H9BrCl2O3

Cl

10

64

125

C20H12BrClO3

S. No

R

R1

R2

5a

Cl

H

5b

CH3

H

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(Calcd) (%) Found

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C 52.30 (52.33) 57.60 (57.79)

H O 2.03 11.00 (2.08) (11.01) 2.89 11.52 (2.91) (11.55)

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5c

Cl

Cl

Br

12

72

123

C19H8Br2Cl2O3

5d

Cl

Cl

H

12

65

112

C19H9BrCl2O3

5e

Cl

NO2

CH3

10

67

120

C20H11BrClNO 5

5f

CH3

Br

Cl

12

64

120

C20H11Br2ClO3

5g

Cl

Br

Cl

10

75

240

C19H8Br2Cl2O3

5h

CH3

Br

CH3

10

62

230

C21H14Br2O3

5i

Cl

H

12

62

130

NH

C19H11BrClNO

2

5j

CH3

H

CH3

3

12

64

255

C21H15BrO3

44.28 (44.31) 52.35 (52.33) 52.16 (52.15) 48.60 (48.57) 44.27 (44.31) 52.16 (53.20) 54.67 (54.77) 63.83 (63.81)

1.60 (1.57) 2.10 (2.08) 2.39 (2.41) 2.26 (2.24) 1.53 (1.57) 2.92 (2.98) 2.56 (2.66) 3.85 (3.83)

9.28 (9.32) 11.02 (11.01) 3.02 (3.04) 9.70 (9.71) 9.24 (9.32) 9.89 (10.12) 11.2 (11.52) 12.06 (12.14)

BIOLOGY In Vitro anti-bacterial & anti-fungal activity The newly synthesized compounds 5a-j were tested for their in vitro antimicrobial activity against clinical isolates of Gram-positive bacteria Staphylococcus aureus, Gram-negative bacteria P. fluoures, Escherichia coli and Candida albicans. The primary activities were evaluated at 50 µg/mL DMSO by well-diffusion method [9] using nutrient agar medium. The inoculated plates were incubated at 35OC for 24 hr in case of bacteria and 48 hr in case of fungus. Doxycycline and fluconazole were used as standards. All synthesized compounds exhibited moderate to resistant activity against all microbes. Moderate zone of inhibition was observed against the strains of E. coli, P. fluoures, and S. aureus while compounds 5a-c, e, f displayed significant activity against strains of Candida albicans. The toxicity increased with the increase in concentration of the test solution containing new compounds, suggesting a maximum tolerated dose. Some compounds did not meet the conventional bacteriostatic standards at lower concentration levels. The variance in the effectiveness of different compounds against different organisms depends either on the impermeability of the cells of the microbes or diffusion in ribosomes of microbial cells [10]. Results obtained after screening the synthesized compounds against various micro-organisms are shown in table 6.

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Table 6. Anti- bacterial & anti-fungal activity of compounds 5a-j. Entry Compounds S.aureus 1. 11 5a 2. 11 5b 3. 10 5c 4. 11 5d 5. 12 5e 6. 10 5f 7. 11 5g 8. 14 5h 9. 12 5i 10. 11 5j D 23 F D= Doxycycline, F= Fluconazole

E.coli 8 8 7 9 8 8 9 7 7 8 14 -

P. fluoures 7 8 7 8 9 8 8 7 7 8 -

C. albicus 12 14 14 10 13 12 10 10 12 13 17

EXPERIMENTALS Melting points were determined by open capillary method and are uncorrected. All solvents were distilled prior to use. TLC was performed on silica gel G. The 1H NMR spectra were recorded on a Brucker AC 400 (MHz) in DMSO-d6 using TMS as internal reference. The IR spectra were recorded on a Perkin-Elmer 1800 spectrophotometer in the 4000–400 cm-1 range using KBr pellets. General procedure General procedure for synthesis of 6-chloro-3-(3-(5-chloro-2-hydroxyphenyl)-3-oxoprop-1enyl)-4H-chromen-4-one 4a. A mixture of 6-chloro-4-oxo-4H-chromone-3-carbaldehyde (0.01 moles), 1-(5-choro-2hudroxyphenyl)acetophenone (0.01 mole) was taken in toluene were [Bmim]BF4 or [Bmim]PF6 (2 mL) added. The reaction mixture was stirred at room temperature for appropriate time; the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture pours into crushed ice. The solid was filtered, dried and crystallized from acetic acid and alcohol. The yellow crystalline compound was obtained (yield 65%). The product was purified using column chromatography with silica-gel and n-hexane/EtOAc (7:3), if necessary. IR (KBr, cm-1) : 1575, 1645, 1670, 2930, 3450 ; 1H NMR (DMSO-d6) : δ 6.90-6.92 (d, 1H, J= 8.92Hz, Ar-Hh), 7.08-7.09 (d, 1H, J= 2.68Hz, Hc), 7.31-7.39 (2dd, 1H, Hi &Hb ), 7.65-

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7.69 (d, 1H, J=15.4Hz, Hg), 7.78-7.80 (d, 1H, J= 9.2Hz, Ha), 7.88-7.88 (d, 1H, J= 2.52Hz, Hj), 8.21-8.25 (d, 1H, J= 15.44Hz, Hf ), 8.46 (s, 1H, Hd ), 12.47 (s, 1H, Ar-OH) ; MS: m/z 361 . 3-(3-(5-chloro-2-hydroxyphenyl)-3-oxoprop-1-enyl)-6-methyl-4H-chromen-4-one 4b IR (KBr, cm-1) : 695, 1675, 1890, 3500; 1H NMR (DMSO-d6) : δ 1.49 (s, 3H, CH3), 6.806.81 (d, 1H, J= 1.56Hz), 7.05-7.09 (d, 1H, J= 3.88Hz), 7.24-7.29 (dd, 1H, Hb), 7.63-7.68 (d, 1H, J= 18.16Hz), 7.76-7.78 (d, 1H, J= 10.6Hz), 7.89-7.90 (dd, 1H), 7.99-8.02 (d, 1H, J= 10.6Hz), 8.47 (s, 1H, Hd), 11.30 (s, 1H, Ar-OH); MS: m/z 341 3-(3-(5-bromo-3-chloro-2-hydroxyphenyl)-3-oxoprop-1-enyl)-6-chloro-4H-chromen-4one 4c IR (KBr, cm-1) : 1635, 1665, 3035; 1H NMR (DMSO-d6) : δ 7.01-7.03 (d, 1H, J= 8.32Hz), 7.29-7.33 (dd, 1H, Hb), 7.58-7.59 (d, 1H, J=4.04Hz, Hc), 7.85-7.86 (d, 1H, J= 6.04Hz, Ha), 8.01-8.04 (d, 1H, J= 11.92Hz, Hg), 8.12-8.15 (d, 1H, J= 12.08Hz, Hf), 8.27 (s, 1H, Hd), 11.50 (s, 1H, Ar-OH); MS: m/z 440; 6-chloro-3-(3-(3-chloro-2-hydroxyphenyl)-3-oxoprop-1-enyl)-4H-chromen-4-one 4d IR (KBr, cm-1) : 650, 1645, 1705, 3430; 1H NMR (DMSO-d6) : 6.29-6.34 (dd, 2H, Hi&j), 7.13-7.15 (d, 2H, J= 8.64Hz, Hg), 7.26-7.27 (d, 1H J= 2.48Hz, Hc), 7.39-7.41 (dd, 1H, Hb), 7.75-7.76 (d, 1H, J= 2.08Hz, Ha), 7.84-7.86 (d, 1H, J= 9.24Hz, Hf), 8.24 (s, 1H, Hd), 10.09 (s, 1H, Ar-OH); MS: m/z 361 6-chloro-3-(3-(2-hydroxy-5-methyl-3-nitrophenyl)-3-oxoprop-1-enyl)-4H-chromen-4-one 4e IR (KBr, cm-1) : 735, 1610, 1680, 2980, 3530; 1 H NMR (DMSO-d6) : δ 1.52 (s, 3H, CH3), 2.16 (s, 3H, Ar-CH3), 6.90-6.92 (d, 1H, J= 8.36Hz, Hc), 7.09-7.09 (d, 1H, J=2.6Hz, Hg),7.31-7.34 (dd, 1H, Hb), 7.62-7.64 (d, 1H, J= 8.36Hz, Hi), 7.75-7.76 (d, 1H, J= 6.4Hz, Ha), 7.87-7.88 (d, 1H, J= 2.96Hz, Hf), 8.21-8.25 (d, 1H, J= 15.52Hz, Hj, ), 8.46 (s, 1H, Hd), 12.31 (s, 1H, Ar-OH); MS: m/z 386 3-(3-(3-bromo-5-chloro-2-hydroxyphenyl)-3-oxoprop-1-enyl)-6-methyl-4H-chromen-4one 4f IR (KBr, cm-1) : 689.3, 1690, 2910, 3450; 1H NMR (DMSO-d6) : δ 1.42 (s, 3H, CH3), 7.017.03 (d, 1H, J= 8.8Hz, Hc), 7.2-7.3 (dd, 1H, Hi), 7.5-7.6 (dd, 1H, Hb), 7.85-7.86 (d, 1H, J=

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6.04Hz, Hg), 8.01-8.04 (d, 1H, J= 11.92Hz, Ha), 8.12-8.15 (d, 1H, J= 8.56Hz, Hf), 8.27 (s, 1H, Hd ), 11.5 (s, 1H, Ar-OH); MS: m/z 419; 3-(3-(3-bromo-5-chloro-2-hydroxyphenyl)-3-oxoprop-1-enyl)-6-chloro-4H-chromen-4one 4g IR (KBr, cm-1) : 1585, 1655, 1675, 3495; 1H NMR (DMSO-d6) : δ 6.77-6.78 (d, 1H, J= 4.88Hz), 7.31-7.34 (dd, 1H, Hb), 7.41-7.42 (d, 1H, J= 4.08Hz, Hg), 7.72-7.75 (d, 1H, J= 13.9Hz, Ha), 7.78-7.79 (d, 1H, J= 4.08Hz, Hf), 7.87-7.88 (d, 1H, J= 4.66Hz, Hi), 8.18-8.19 (d, 1H, J= 2.64Hz, Hj), 8.42 (s, 1H, Hd), 11.83 (s, 1H, Ar-OH); MS: 3-(3-(3-bromo-2-hydroxy-5-methylphenyl)-3-oxoprop-1-enyl)-6-methyl-4H-chromen-4one 4h IR (KBr, cm-1) : 695, 1590, 1680, 2988, 3490; 1H NMR (DMSO-d6) : δ 2.16 (s, 6H, -CH3), 6.95-6.96 (d, 1H, J= 2.76Hz, Hc), 7.20-7.20 (d, 1H, J= 2.98Hz, Ha), 7.38-7.39 (dd, 1H, Hb), 7.73-7.77 (d, 1H, J= 15.52Hz, Hg), 7.85-7.87 (d, 1H, J= 9.2Hz, Hi), 7.9-8.03 (m, 1H, Ar-H), 8.09-8.13 (d, 1H, J= 15.68Hz, Hf), 8.57 (s, 1H, Hd), 11.96 (s, 1H, Ar-OH); MS: m/z 399 3-(3-(5-amino-2-hydroxyphenyl)-3-oxoprop-1-enyl)-6-chloro-4H-chromen-4-one 4i IR (KBr, cm-1) : 725, 1610, 1710, 3550; 1H NMR (DMSO-d6) : δ 5.3 (s, 2H, Ar-NH2), 7.397.39 (d, 1H, J= 2.32Hz, Hc), 7.50-7.53 (dd, 1H, Hb), 7.67-7.69 (d, 1H, J= 8.88Hz, Hg), 7.787.81 (dd, 1H, Hi), 7.92-7.94 (d, 1H, J= 9.04Hz, Hf), 8.09-8.09 (d, 1H, J= 2.4Hz, Hj, ), 8.63 (s, 1H, Hd), 9.6 (s, 1H, Ar-OH); MS: m/z 341 3-(3-(2-hydroxy-5-methylphenyl)-3-oxoprop-1-enyl)-6-methyl-4H-chromen-4-one 4j IR (KBr, cm-1) : 1600, 1645, 2900, 3000, 3400; 1H NMR (DMSO-d6) : δ 2.38 (s, 6H, -CH3), 6.96-6.98 (d, 1H, J= 8.48Hz, Hh), 7.14-7.15 (d, 1H, J= 2.68Hz, Hc), 7.35-7.44 (2dd, 1H, Hi & Hb), 7.71-7.75 (d, 2H, J= 15.56Hz, Ha), 7.91-7.94 (d, 1H, J= 9.2Hz, Hg), 8.27-8.30 (d, 1H, J= 15.48Hz, Hf), 8.39 (s, 1H, Hd), 12.51 (s, 1H, Ar-OH) ; MS: m/z 320 General procedure for synthesis of 3-(2-bromo-7-chloro-1,4-dihydro-1-oxonaphthalen3-yl)-6-chloro-4H-chromen-4-one 5a. A mixture of 6-chloro-3-(3-(5-chloro-2-hydroxyphenyl)-3-oxoprop-1-enyl)-4H-chromen-4one, cupper bromide in DMSO was taken in a conical flask covered with filter funnel. The reaction mixture was irradiated in microwave oven (domestic) at 1450C for 10-12 min. The reaction periods were standardized by irradiating the reaction mixtures in 1-6 cycles, each of

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2min interval and 1min rest. The progress of reaction was monitor by TLC (in each 2 min interval). After cooling to room temp., the solvent was evaporated and the residue was extracted in ethyl acetate (10mL x 3) and dried over Na2SO4. The organic layer was evaporated on rotary evaporator solid mass obtained. IR (KBr, cm-1) : 1670, 2930-3070, 750 cm-1 ; 1 H-NMR (DMSO-d6) : δ7.02-7.04 (dd, 1H, J=9.36 Hz, Hd), 7.11-7.12 (dd, 1H, Hi), 7.26-7.27 (d, 1H, J=2.48 Hz, Hc), 7.75-7.76 (d, 1H, J=2.08 Hz, Hj), 7.84-7.86 (d, 1H, J=9.24 Hz, Ha), 8.0 (s, 1H, Hd); 13C-NMR(DMSO-d6) δ: 16.89, 96.23, 116.71, 119.00, 123.78, 125.30, 128.93, 132.98, 138.82, 141.21, 141.44, 145.12, 147.04, 158.0, 169.82, 174.03; MS (m/z): 436 M+ 3-(2-bromo-7-chloro-1,4-dihydro-1-oxonaphthalen-3-yl)-6-methyl-4H-chromen-4-one 5b IR (KBr, cm-1) : 3150, 2978, 1680, 1510, 775cm-1 ; 1H-NMR (DMSO-d6) : δ 1.22 (s, 3H, CH3), 6.88-6.89 (d, 1H, J=3.8Hz, Hc), 7.15-7.17 (d, 1H, J=7.76Hz, Ha), 7.33-7.37 (dd, 1H, Hb), 7.89-7.91 (d, 1H, J=7.32Hz), 8.00 (s, 1H, Hh), 8.45 (s, 1H, Hd); 13C-NMR(DMSO-d6) δ: 18.2, 102.1, 105.8, 106.7, 118.2, 122.3, 126.3, 127.8, 128.2, 131.2, 133.3, 142.3, 145.2, 158.3, 165.2, 168.5, 174.5; MS (m/z): 416 M+ 3-(2,7-dibromo-5-chloro-1,4-dihydro-1-oxonaphthalen-3-yl)-6-chloro-4H-chromen-4one 5c IR (KBr, cm-1) : 3080, 1702, 1603, 1645,680, 565cm-1 ; 1H-NMR (DMSO-d6) : 7.04-7.05 (d, 1H, J=3.92Hz, Hc), 7.30-7.34 (dd, 1H, Hb), 7.57-7.59 (d, 1H, J=7.6Hz, Hi), 7.64-7.66 (d, 1H, J=9.17Hz, Hj), 7.84-7.87 (d, 1H, J=14.52Hz, Ha), 8.00 (s, 1H, Hd); 13C-NMR(DMSO-d6) δ: 103.4, 107.2, 118.1, 125.3, 128.2, 128.6, 129.3, 132.2, 133.4, 137.8, 138.9, 143.3, 147.8, 153.5, 167.2, 172.8; MS (m/z): 515 M+ 3-(2-bromo-5-chloro-1,4-dihydro-1-oxonaphthalen-3-yl)-6-chloro-4H-chromen-4-one 5d IR (KBr, cm-1) : 2991, 1690, 1590, 680cm-1 ; 1H-NMR (DMSO-d6) : δ 6.85-6.86 (d, 1H, J=4.92Hz, Hj ), 7.05-7.06 (d, 1H, J=2.68Hz, Hc), 7.26-7.35 (m, 2H, He), 7.61-7.65 (d, 1H, J=15.4Hz, Hi), 7.75-7.78 (d, 1H, J=13.2Hz, Ha), 7.84 (s, 1H, Hd); 13C-NMR(DMSO-d6) δ: δ 101.4, 107.5, 124.2, 125.5, 128.7, 132.5, 135.3, 136.2, 136.7, 137.5, 143.2, 149.8, 152.4, 170.1, 175.3; MS (m/z): 436.03 M+

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3-(2-bromo-1,4-dihydro-7-methyl-5-nitro-1-oxonaphthalen-3-yl)-6-chloro-4H-chromen4-one 5e IR (KBr, cm-1) : 3101, 2990, 1962, 680cm-1; 1H-NMR (DMSO-d6) : δ 1.88 (s, 3H, -CH3), 7.12-7.14 (d, 1H, J=7.12Hz, Ha), 7.30-7.30 (d, 1H, J=3.48Hz, Hc), 7.56-7.59 (dd, 1H, Hb), 7.89-7.90 (d, 1H, J=5.4Hz, Hj), 8.00-8.02 (d, 1H, J=8.2Hz, Hi), 8.11 (s, 1H, Hd);

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NMR(DMSO-d6) δ: 20.3, 100.8, 103.8, 122.5, 123.3, 125.5, 128.1, 130.9, 135.2, 138.3, 141.5, 148.2, 149.3, 169.5, 179.3; MS (m/z): 460.7 M+ 3-(2,5-dibromo-7-chloro-1,4-dihydro-1-oxonaphthalen-3-yl)-6-methyl-4H-chromen-4one 5f IR (KBr, cm-1) : 2983, 1696, 1342, 668cm-1; 1H-NMR (DMSO-d6) : δ 1.59 (s, 3H,- CH3), 6.84-6.85 (d, 1H, J=6.88Hz, Ha), 7.07-7.10 (dd, 1H, Hb), 7.37-7.38 (d, 1H, J- 3.76Hz, Hj), 7.43-7.44 (d, 1H, J=3.04Hz, Hc), 7.62-7.65 (d, 1H, J=14.72, Hh), 7.80 (s, 1H);

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NMR(DMSO-d6) δ: δ 14.5, 90.7, 102.3, 106.8, 122.3, 127.0, 129.3, 127.3, 131.1, 133.1, 142.5, 144.3, 147.2, 152.2, 155.2, 172.5; MS (m/z): 494.14 M+ 3-(2,5-dibromo-7-chloro-1,4-dihydro-1-oxonaphthalen-3-yl)-6-chloro-4H-chromen-4one 5g IR (KBr, cm-1) : 2900, 1610, 1530, 1340, 725, 675cm-1 ; 1H-NMR (DMSO-d6) : δ 6.74-6.76 (d. 1H, J=7.32Hz, Hi), 7.23-7.29 (dd, 1H, Hb), 7.39-7.39 (d, 1H, J=2.48Hz), 7.69-7.72 (d, 1H, J=14.00Hz, Ha), 7.77-7.79 (d, 1H, J= 7.68Hz, Hj), 7.85 (s, 1H, Hd); 13C-NMR(DMSOd6) δ: 102.1, 107.7, 117.2, 124.2, 128.7, 129.2, 131.3, 132.4, 133.5, 136.4, 138.5, 143.2, 147.6, 153.3, 170.2, 175.1; MS (m/z): 515.14 M+ 3-(2,5-dibromo-1,4-dihydro-7-methyl-1-oxonaphthalen-3-yl)-6-methyl-4H-chromen-4one 5h IR (KBr, cm-1) : 3120, 2999, 769cm-1; 1H-NMR (DMSO-d6) : δ1.67 (s, 6H, -CH3), 6.77-6.79 (d, 1H, J=8.52Hz, Hj), 7.03-7.04 (d, 1H,J=3.24Hz, Hi), 7.22-7.25 (dd, 1H, Hb), 7.53-7.57 (d, 1H, J=15.52Hz, Ha), 7.64-7.67 (d, 1H, J=11.88Hz), 7.79-7.81 (m, 1H), 8.89 (s, 1H, Hd); 13CNMR(DMSO-d6) δ: 22.2. 99.7, 103.8, 114.9, 124.3, 126.4, 128.9, 130.1, 131.1, 132.2, 135.3, 140.5, 143.6, 147.5, 152.3, 170.3, 174.1; MS (m/z): 474.29 M+ 3-(7-amino-2-bromo-1,4-dihydro-1-oxonaphthalen-3-yl)-6-chloro-4H-chromen-4-one 5i IR (KBr, cm-1) : 3370, 3010, 1390, 670cm-1 ; 1H-NMR (DMSO-d6) : δ 5.30 (s, 2H, Ar-NH2), 7.39-7.39 (d, 1H, J=3.64Hz), 7.50-7.53 (dd, 1H, Hb), 7.67-7.69 (d, 1H, J=8.88Hz, Ha), 7.787.79 (1H, d, J=2.36Hz, Hc), 7.81-7.81 (d, 1H, J=2.44Hz, Hj), 7.92-7.94 (d, 1H, J=8.96Hz, www.wjpr.net

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Hi), 8.02 (s, 1H, Hd); 13C-NMR(DMSO-d6) δ: δ 167.1, 103.3, 108.4, 117.3, 118.5, 122.5, 125.3, 127.8, 129.2, 132.4, 136.3, 142.7, 148.3, 148.8, 157.1, 171.2; MS (m/z): 417.08 M+ 3-(2-bromo-1,4-dihydro-7-methyl-1-oxonaphthalen-3-yl)-6-methyl-4H-chromen-4-one 5j IR (KBr, cm-1) : 3110, 1690,1629, 788cm-1 ; 1H-NMR (DMSO-d6) : δ1.72 (s, 6H, -CH3), 7,287.30 (d, 1H, J=8.96Hz, Ha), 7.47-7.48 (d, 1H, J=5.24Hz, ), 7.66-7.69 (dd, 1H, Hb), 7.73-7,76 (dd, 1H, Hi), 8.03-8.07 (d, 2H, J=17.4, Hh), 8.25 (s, 1H, Hd); 13C-NMR(DMSO-d6) δ: 24.3, 98.23, 105.6, 117.6, 123.9, 129.0, 131.0, 130.1, 134.4, 135.6, 133.1, 142.7, 147.2, 154.3, 168.00, 173.01; MS (m/z): 395.08 M+ CONCLUSION In summary, a synthesis of chromone based substituted 3-(3-bromo-4-oxo-4H-chromen-2yl)-4H-chromen-4-one compounds (5a-j) using at 140oC microwave oven (domestic) DMSO, without any special activation was well examined. From the experimental evidences of influence of molar conc. of [Et3NH][HSO4], temperature, time was also recorded in case of (4b) at 1000C in toluene. The recycling efficiency of ionic liquid was found to be decreased after each cycle. With this facile method, we achieved maximum yield. This method works with a wide variety of primary as well as secondary amines and aldehydes. The mild reaction conditions, cheap and easily available raw material required for ionic liquids and simplicity of the reaction procedure and dual nature of recyclable ionic liquids will certainly attract attention among organic chemists. ACKNOWLEDGEMENTS Authors are thankful to the Department of Pharmacy, Nagpur for IR spectral analysis and SAIF, Chandigarh for 1H NMR spectral analysis. We also wish to extend our gratitude to SAIF, Pune University for mass spectral analysis of all new synthesized compounds. We pay special thanks to Dr. Mrs. Sandhya Saoji for antitubercular activity and other biological assays REFERENCES 1. (a) Harborne JB, Williams CA. Phytochemistry 2000; 55; 481. (b) Houghton PJ. Stud. Nat. Prod. Chem. 2000; 21; 123. (c) Xiao D, Kuroyanagi M, Itani T, Matsuura H,

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